Enhanced monitoring of vaccine safety for 2009 pandemic vaccines

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Updated 15 August 2013

Mass vaccination campaigns using newly developed monovalent pandemic A(H1N1) vaccines were initiated in a number of countries worldwide starting progressively from late September 2009. See ECDC Pandemic Timeline.A range of vaccines based on different technologies were purchased by European (EU, EEA and EFTA) countries.

Three pandemic vaccines were authorised through the central procedure in the EU under the European Medicines Agency and the European Commission; Pandemrix, Focetria and Celvapan.

Two pandemic vaccines were authorised for national use in Hungary (Fluval P) and in Romania (Cantgrip).

Three pandemic vaccines were authorised nationally and through mutual recognition (Panenza, Celtura andPanvaxH1N1).

Hence the vaccines used differed between European countries. The final recommended target groups for vaccination also differed. A number of countries had the option of offering the pandemic vaccines to their entire population on the basis of contracts. Some exercised this option, but others did not. Most recommended vaccination of certain risk groups broadly following the recommendations of WHO and the European Health Security Committee, which was working in the light of ECDC guidance. Some Member States offered one single vaccine to their risk/target groups or to the wider population, depending on their vaccination approach. Other countries offered several vaccines, resulting in different vaccines offered to different risk/target groups.

Authorisation of new centrally authorised vaccines is regulated in the European Union through the European Medicine Agency (EMA). This takes place following assessment of safety and immunogenicity in clinical trials. Common adverse events (occurring in more than 1/100 vaccinated individuals) can be identified in pre-licensure clinical trials. The EMA is also the primary EU authority for monitoring safety of centrally authorised vaccines. For more rare adverse events (occurring in less than 1/1,000 vaccinated individuals) routine monitoring of adverse events following immunisation (AEFIs) in the post-authorisation period is undertaken. Very rare events (occurring in less than 1/10,000 vaccinated individuals) may only be identified when vaccines are introduced in larger populations. Routine monitoring of AEFIs are therefore essential and performed in all EU, EEA and EFTA Member States however, under-reporting by professionals has to be accepted as a reality and allowed for.

ECDC supports the vaccine safety monitoring systems organized by EMA and Member States within the limits of its mandate of risk assessment, surveillance and technical guidance. This is done by sharing best practices of enhanced monitoring and by sometimes investigating reported suspected AEFIs, including identification and assessment of any vaccine safety signals. This work is undertaken in close collaboration with Member State authorities, the EMA, the European Commission and the World Health Organisation. This is reviewed by an EU Vaccines Task Force. In preparation for this ECDC identified Member States with capacity to establish enhanced monitoring of vaccine safety and likely to be able to investigate should a vaccine safety signal arise.Consequently a network of researchers (VAESCO - Vaccine Adverse Events Surveillance and Communication) in nine Member States was established initially to estimate background incidence rates of medical events that possibly could be associated with administration of pandemic vaccines and then to investigate potential signals. This enhanced monitoring and investigation of vaccine safety was entirely funded at a European level by ECDC and directed scientifically by the VAESCO consortium and ECDC.

The VAESCO network was asked by ECDC to investigate a possible association between Guillain-Barré syndrome and the pandemic vaccines used in Europe in the winter season 2009/2010. This was undertaken prospectively because another swine origin influenza A(H1N1) vaccine - subtype A/NJ/76 vaccine – developed and used in the U.S. in 1976 in anticipation of a pandemic – was found to be associated with an increased number of GBS cases. Consequently vaccination was stopped abruptly. Though subsequent studies have repeatedly found little or no association between the different seasonal influenza vaccines and GBS during later seasons the 2009/2010 study was initiated to exclude a similar association with the 2009 pandemic vaccines. Similar studies were carried out throughout the world; eg the US, Canada, Australia, Japan, Taiwan, Singapore etc. In addition, following the safety signal of narcolepsy after vaccination with one of the adjuvanted pandemic vaccines (Pandemrix) the network was asked by ECDC to investigate a possible association.

Guillain-Barré syndrome (GBS)

For GBS a multi-country case control study was undertaken in 2009/2010. Centres in Denmark, France, the Netherlands, Sweden and the UK participated in this study. The study found that the risk of occurrence of GBS was not increased after administration of adjuvanted pandemic influenza vaccines (Pandemrix and Focetria) and the results were published in July 2011. The pattern was consistent across the five countries.

Following the first vaccine safety signal of narcolepsy (reported in August 2010), VAESCO is undertaking a similar multi-country case control study to test whether a true association between the used 2009 pandemic vaccine Pandemrix and narcolepsy is being seen in Europe. Centres in Denmark, Finland, France, Italy, the Netherlands, Norway, Sweden and the UK are participating in the study.

The GSK H1N1 AS03-adjuvanted vaccine Pandemrix (produced in Germany) was used in more than 47 countries starting October 2009; high coverage was obtained in some countries (eg Finland, Sweden, Norway, and Ireland). Another GSK H1N1 AS03-adjuvanted vaccine Arepanrix (produced in Canada) was used in Canada and several other countries starting October 2009; high coverage was obtained in Canada and as of now no similar safety signal has been reported following vaccination with this vaccine.

An estimated 30.8 million doses of Pandemrix were administered in the EU during the 2009/2010 pandemic influenza season. An estimated 12 million doses of Arepanrix were administered in Canada during the same winter season.

ECDC issues sixth piece of scientific advice on Irish investigation of an increase in the incidence of narcolepsy in children and adolescents in 2009 and 2010 – final report of national narcolepsy study steering committee

Second ECDC/VAESCO vaccine safety study initiated to investigate background rates of narcolepsy in the EU and conduct a multi-country association study (case control methodology) to assess a possible association between pandemic vaccines and development of narcolepsy.

Recommendation by WHO to switch back to use of triple seasonal influenza vaccines including the new A(H1N1)pdm09 and previous A(H3N2) and B-Victoria like vaccine virus for the Northern Hemisphere 2010-2011. Manufacturers start producing accordingly and decide to generally revert to not using adjuvants as extensively as they did with the pandemic vaccines.

Crude background incidence rates of specified medical events of interest selected by EMA and FDA to allow for timely estimations of observed versus expected number of cases, should a vaccine safety signal arise shared with EMA (not in the public domain).

ECDC/VAESCO initiates the first prospective vaccine safety studies to exclude an association with current vaccines between swine-influenza based vaccines and development of Guillain-Barré syndrome due to an earlier association identified in 1976 when a swine-influenza based vaccine was used:

From September 2009 five pandemic vaccines authorised through the central procedure in the EU; Pandemrix, Focetria, Celvapan. Humenza and Arepanrix. In addition, two unadjuvanted pandemic vaccines were authorised for national use in Hungary (Fluval P) and in Romania (Cantgrip). Finally, another three unadjuvanted pandemic vaccines were authorised nationally and through mutual recognition (Panenza, Celtura and PanvaxH1N1).

* Since new technologies were involved in the production of some pandemic vaccines, which had not yet been extensively evaluated for their safety in certain population groups, it was very important to implement post-marketing surveillance of the highest possible quality. In addition, rapid sharing of the results of immunogenicity and post-marketing safety and effectiveness studies among the international community was viewed as essential for allowing countries to make necessary adjustments to their vaccination policies.